Strattera

STRATTERA may be taken with or without food.

Consumption of ethanol with STRATTERA did not change the intoxicating effects of ethanol.

STRATTERA (atomoxetine hydrochloride) is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. In extensive metabolizers (EMs), inhibitors of CYP2D6 (e.g., paroxetine, fluoxetine, quinidine) increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in poor metabolizers (PMs). Dosage adjustment of STRATTERA may be necessary when coadministered with CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine (see Dosage and Administration). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and C_ss,max is about 3- to 4-fold greater than atomoxetine alone.

In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not further increase the plasma concentration of atomoxetine.

Atomoxetine did not cause clinically significant inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9.

Drugs that affect norepinephrine should be used cautiously when co-administered with STRATTERA because of the potential for additive or synergistic pharmacological effects.

In children (≥6 years old) and adolescents up to 70 kg body weight administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, STRATTERA should be initiated at 0.5 mg/kg/day and only increased to the next dose level if symptoms fail to improve after 14 days and the previous dose is well tolerated.

In children (≥6 years old) and adolescents over 70 kg body weight and adults administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, STRATTERA should be initiated at 40 mg/day and only increased to the next dose level if symptoms fail to improve after 14 days and the previous dose is well tolerated.

Theoretically there exists a pharmacological potential for all ADHD drugs to increase the risk of sudden/cardiac death. Although confirmation of an incremental risk for adverse cardiac events arising from treatment with ADHD medications is lacking, prescribers should consider this potential risk.

All drugs with sympathomimetic effects prescribed in the management of ADHD should be used with caution in patients who: a) are involved in strenuous exercise or activities, b) use stimulants, or c) have a family history of sudden/cardiac death. Prior to the initiation of treatment with sympathomimetic medications, a personal and family history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam should be obtained to assess for the presence of cardiac disease. In patients with relevant risk factors and based on the clinician’s judgment, further cardiovascular evaluation may be considered (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during ADHD treatment should undergo a prompt cardiac evaluation. Patients who are considered to need extended treatment with STRATTERA should undergo periodic evaluation of their cardiovascular status (see Warnings and Precautions).

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring of agitation-type emotional and behavioural changes, and clinical worsening (see Warnings and Precautions, Potential Association with the Occurrence of Behavioural and Emotional Changes, Including Self-Harm).

STRATTERA (atomoxetine hydrochloride) is intended for oral administration and may be taken with or without food, either as a single daily dose in the morning or as divided doses in the morning and late afternoon/early evening.

Initial improvement of ADHD symptoms is generally observed within 1 to 4 weeks of initiating therapy.

STRATTERA did not worsen tics in pediatric patients, and may be used in patients with ADHD and comorbid motor tics or diagnosis of Tourette's Disorder. STRATTERA did not worsen anxiety in either pediatric or adult patients, and may be used in patients with ADHD and comorbid anxiety disorders. See Action and Clinical Pharmacology, Special Populations and Conditions, Patients with Concomitant Illness.

If patients miss a dose, they should take it as soon as possible; however, they should not take more than the prescribed total daily amount of STRATTERA in any 24-hour period.

STRATTERA may be discontinued without tapering the dose.

Pharmacological treatment of ADHD may be needed for extended periods. The efficacy of STRATTERA in maintaining symptom response during long-term treatment in children and adolescents was studied in an 18-month trial (3 months of acute open-label treatment followed by up to 15 months of placebo-controlled maintenance treatment). The results from this study suggest that atomoxetine may be beneficial in the long-term treatment of ADHD. Too few patients completed the study to permit an adequate assessment of the long-term safety profile of STRATTERA in this study. The long-term safety of STRATTERA has been demonstrated in double-blind and open-label clinical trials of at least 24 months. The physician who elects to use STRATTERA for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see Indications and Clinical Use).

Do not exceed the recommended initial dose and subsequent dose escalations of STRATTERA. Do not exceed the recommended maximum total daily dose of 100 mg. The safety of single doses over 120 mg and total daily doses above 150 mg have not been systematically evaluated and therefore should not be administered because of potential side effects (see Action and Clinical Pharmacology, Cardiovascular Safety and Overdosage).

STRATTERA should be initiated at a total daily dose of 40 mg. The initial dose should be maintained for 7 to 14 days. After this time, if patients have not experienced clinically significant symptom response at the initial dose, the dose may be increased to the intermediate dose level of 60 mg, which also should be maintained for 7 to 14 days. According to clinical response and tolerability, the dose may be increased to 80 mg. After 2 to 4 additional weeks, the total daily dose may be increased to a maximum of 100 mg in patients who have not achieved an optimal response.

The maximum recommended total daily dose in children and adolescents over 70 kg and adults is 100 mg.

STRATTERA should be administered starting at the lowest possible dose. Dosage should then be individually and slowly adjusted to the lowest effective dose, since individual patient response to STRATTERA varies widely.

STRATTERA should not be used in patients with symptomatic cardiovascular disease and should not generally be used in patients with known structural cardiac abnormalities (see Contraindications and Warnings and Precautions).

Subjects with end stage renal disease had higher systemic exposure to atomoxetine than healthy subjects (about a 65% increase), but there was no difference when exposure was corrected for mg/kg dose. STRATTERA can therefore be administered to ADHD patients with end stage renal disease or lesser degrees of renal insufficiency using the usual dosing regimen. Atomoxetine may exacerbate hypertension in patients with end stage renal disease.

Atomoxetine clearance may be reduced in ADHD patients with hepatic impairment. For patients with moderate hepatic impairment (Child-Pugh Class B), initial and target doses should be reduced to 50% of the normal dose. For patients with severe hepatic impairment (Child-Pugh Class C), initial dose and target doses should be reduced to 25% of the normal dose.

In post-market experience, serious skin reactions were reported at a spontaneous reporting rate less than 0.001%.

The following adverse events occurred in at least 2% of PM patients and were either twice as frequent or statistically significantly more frequent in PM patients compared with EM patients: appetite decreased (24% of PMs, 17% of EMs); insomnia and middle insomnia (14% of PMs, 8% of EMs); sedation (4% of PMs, 2% of EMs); depression and/or depressed mood (5% of PMs, 3% of EMs); abrasion (4% of PMs, 2% of EMs); tremor (5% of PMs, 1% of EMs); early morning awakening (2% of PMs, 1% of EMs); enuresis (3% of PMs, 1% of EMs); pruritus (3% of PMs, 1% of EMs); mydriasis (2% of PMs, 1% of EMs); conjunctivitis (3% of PMs, 1% of EMs); syncope (2% of PMs, 1% of EMs); animal bite (2% of PMs, 1% of EMs).

STRATTERA is not a controlled substance.

STRATTERA is not a stimulant drug. In a randomized, double-blind, placebo-controlled, abuse-potential study in adults comparing effects of STRATTERA and placebo, STRATTERA was not associated with a pattern of response that suggested stimulant or euphoriant properties.

Clinical trials data in over 4000 children, adolescents, and adults with ADHD showed only isolated incidents of drug diversion or inappropriate self-administration associated with STRATTERA. There was no evidence of symptom rebound or adverse events suggesting a drug-discontinuation or withdrawal syndrome.

In preclinical studies, atomoxetine did not show a behavioural profile or stimulant properties associated with drugs that have abuse liability.

In acute child and adolescent placebo-controlled trials, 4.1% (27/661) of atomoxetine subjects and 1.2% (5/410) placebo subjects discontinued for adverse events. For all studies, (including open-label and long-term studies), 5.8% of extensive metabolizer (EM) patients and 8.9% of poor metabolizer (PM) patients discontinued because of an adverse event. Among STRATTERA-treated patients, somnolence (0.8%, N=5); aggression (0.5%, N=3); irritability (0.5%, N=3); vomiting (0.5%, N=3) and abdominal pain (0.3%, N=2) were the reasons for discontinuation reported by more than 1 patient.

In the acute adult placebo-controlled trials, 8.5% (23/270) atomoxetine subjects and 3.4% (9/266) placebo subjects discontinued for adverse events. Among STRATTERA-treated patients, insomnia (1.1%, N=3); chest pain (0.7%, N=2); palpitations (0.7%, N=2); and urinary retention (0.7%, N=2) were the reasons for discontinuation reported by more than 1 patient.

There are no adequate and well-controlled studies examining sexual dysfunction with STRATTERA treatment. While it is difficult to know the precise risk of sexual dysfunction associated with the use of STRATTERA, physicians should routinely inquire about such possible side effects.

The safety and efficacy of STRATTERA in pediatric patients less than 6 years of age have not been established.

STRATTERA is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, and social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. Drug treatment is not intended for use in the patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential in children and adolescents with this diagnosis and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe drug treatment medication will depend upon the physician's assessment of the chronicity and severity of the patient's symptoms.

The specific etiology of ADHD is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but also of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presence of the required number of DSM-IV characteristics.

There is no established antidote for STRATTERA overdose. Treatment has been supportive, including establishing an airway when necessary, monitoring of cardiac and vital signs, along with appropriate symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after ingestion. Activated charcoal may be useful in limiting absorption. Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose.

Each opaque blue, gold capsule, identified with LILLY 3239, contains: atomoxetine hydrochloride equivalent to 60 mg of atomoxetine. Nonmedicinal ingredients: dimethicone and pregelatinized starch; capsule shell: gelatin, sodium lauryl sulfate, and other inactive ingredients. The capsule shells also contain one or more of the following: FD&C Blue No. 2, red iron oxide, synthetic yellow iron oxide and titanium dioxide. Blisters packages of 28.

Each opaque white, opaque white capsule, identified with LILLY 3227, contains: atomoxetine hydrochloride equivalent to 10 mg of atomoxetine. Nonmedicinal ingredients: dimethicone and pregelatinized starch; capsule shell: gelatin, sodium lauryl sulfate, and other inactive ingredients. The capsule shells also contain one or more of the following: FD&C Blue No. 2, red iron oxide, synthetic yellow iron oxide and titanium dioxide. Blisters packages of 28.

Each opaque blue, opaque blue capsule, identified with LILLY 3229, contains: atomoxetine hydrochloride equivalent to 40 mg of atomoxetine. Nonmedicinal ingredients: dimethicone and pregelatinized starch; capsule shell: gelatin, sodium lauryl sulfate, and other inactive ingredients. The capsule shells also contain one or more of the following: FD&C Blue No. 2, red iron oxide, synthetic yellow iron oxide and titanium dioxide. Blisters packages of 28.

Each gold, opaque white capsule, identified with LILLY 3238, contains: atomoxetine hydrochloride equivalent to 18 mg of atomoxetine. Nonmedicinal ingredients: dimethicone and pregelatinized starch; capsule shell: gelatin, sodium lauryl sulfate, and other inactive ingredients. The capsule shells also contain one or more of the following: FD&C Blue No. 2, red iron oxide, synthetic yellow iron oxide and titanium dioxide. Blisters packages of 28.

Each opaque blue, opaque white capsule, identified with LILLY 3228, contains: atomoxetine hydrochloride equivalent to 25 mg of atomoxetine. Nonmedicinal ingredients: dimethicone and pregelatinized starch; capsule shell: gelatin, sodium lauryl sulfate, and other inactive ingredients. The capsule shells also contain one or more of the following: FD&C Blue No. 2, red iron oxide, synthetic yellow iron oxide and titanium dioxide. Blisters packages of 28.

The safety and efficacy of STRATTERA in pediatric patients less than 6 years of age have not been established.

Theoretically there exists a pharmacological potential for all ADHD drugs to increase the risk of sudden/cardiac death. Although confirmation of an incremental risk for adverse cardiac events arising from treatment with ADHD medications is lacking, prescribers should consider this potential risk.

All drugs with sympathomimetic effects prescribed in the management of ADHD should be used with caution in patients who: a) are involved in strenuous exercise or activities, b) use stimulants, or c) have a family history of sudden/cardiac death. Prior to the initiation of treatment with sympathomimetic medications, a personal and family history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam should be obtained to assess for the presence of cardiac disease. In patients with relevant risk factors and based on the clinician’s judgment, further cardiovascular evaluation may be considered (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during ADHD treatment should undergo a prompt cardiac evaluation. Patients who are considered to need extended treatment with STRATTERA should undergo periodic evaluation of their cardiovascular status (see Dosage and Administration).

Administration of medications for ADHD may also exacerbate symptoms of behaviour disturbance and thought disorder in patients with a pre-existing psychotic disorder.

An increased risk over placebo, for suicide-related events in children and adolescents taking STRATTERA was identified in a combined analysis of 12 short-term (6-18 weeks) placebo-controlled trials (11 in ADHD and 1 in enuresis). Of 1357 patients who received STRATTERA, 5 (0.37%) had reports of suicidal ideation compared to 0% of 851 patients who received placebo. In addition, one suicide attempt (overdose) was identified which occurred in a STRATTERA patient. These 6 events occurred in STRATTERA patients 7 to 12 years of age who were male. There were no events in older adolescents, who comprised about 25 percent of the study population. Time to onset ranged from 9 to 32 days, and doses ranged from 0.48 to 1.40 mg/kg/day. A similar analysis in adult patients treated with STRATTERA for either ADHD or major depressive disorder (MDD) found no increased risk over placebo of suicidal ideation or behaviour with the use of STRATTERA.

Not included in these numerators were 6 cases (3 in the STRATTERA arms and 3 in the placebo arms) of non-fatal potentially self-injurious actions where the intent is unknown, including burns and taking more than one dose of medication at a time.

Pregnant rabbits were treated with up to 100 mg/kg/day of atomoxetine by gavage throughout the period of organogenesis. At this dose, in 1 of 3 studies, a decrease in live fetuses and an increase in early resorptions was observed. Slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery were observed. These findings were observed at doses that caused slight maternal toxicity. The no-effect dose for these findings was 30 mg/kg/day. The 100-mg/kg dose is approximately 23 times the maximum human dose on a mg/m² basis; plasma levels (AUC) of atomoxetine at this dose in rabbits are estimated to be 3.3 times (extensive metabolizers) or 0.4 times (poor metabolizers) those in humans receiving the maximum human dose.

Rats were treated with up to approximately 50 mg/kg/day of atomoxetine (approximately 6 times the maximum human dose on a mg/m² basis) in the diet from 2 weeks (females) or 10 weeks (males) prior to mating through the periods of organogenesis and lactation. In 1 of 2 studies, decreases in pup weight and pup survival were observed. The decreased pup survival was also seen at 25 mg/kg (but not at 13 mg/kg). In a study in which rats were treated with atomoxetine in the diet from 2 weeks (females) or 10 weeks (males) prior to mating throughout the period of organogenesis, a decrease in fetal weight (female only) and an increase in the incidence of incomplete ossification of the vertebral arch in fetuses were observed at 40 mg/kg/day (approximately 5 times the maximum human dose on a mg/m² basis) but not at 20 mg/kg/day. No adverse fetal effects were seen when pregnant rats were treated with up to 150 mg/kg/day (approximately 17 times the maximum human dose on a mg/m² basis) by gavage throughout the period of organogenesis.

Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can occur with atomoxetine use at usual doses. If such symptoms occur, consideration should be given to a possible causal role of atomoxetine, and discontinuation of treatment should be considered. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.2% (4 patients with events out of 1939 exposed to atomoxetine for several weeks at usual doses) of atomoxetine-treated patients compared to 0 out of 1056 placebo-treated patients.

No adequate and well-controlled studies have been conducted in pregnant women. STRATTERA should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. The effect of STRATTERA on labour and delivery in humans is unknown.

The extent of exposure in pregnancy during clinical trials was very limited.

The safety and efficacy of STRATTERA in geriatric patients have not been established.

Clinical trial data in children and adolescents show higher rates than placebo for irritability, mood swings, aggression, crying and tearfulness (see Adverse Reactions, Table 1 and Table 2). The relationship, if any, between these events and suicide-related behaviours in children and adolescents with ADHD is unclear.

Chronic open-label treatment studies (up to 3 years) indicate minimal, if any, long-term effects of STRATTERA on weight and height compared with normal growth curves.

In general, the weight and height gain of pediatric patients treated with STRATTERA lags behind that predicted by normative population data for about the first 9-12 months of treatment. Subsequently, weight gain rebounds and at about 3 years of treatment, patients treated with STRATTERA have gained 17.9 kg on average, 0.5 kg more than predicted by their baseline data. After about 12 months, gain in height stabilizes, and at 3 years, patients treated with STRATTERA have gained 19.4 cm on average, 0.4 cm less than predicted by their baseline data.

This growth pattern was generally similar regardless of pubertal status at the time of treatment initiation. Patients who were pre-pubertal at the start of treatment (girls ≤8 years old, boys ≤9 years old) gained an average of 2.1 kg and 1.2 cm less than predicted after three years. Patients who were pubertal (girls >8 to ≤13 years old, boys >9 to ≤14 years old) or late pubertal (girls >13 years old, boys >14 years old) had average weight and height gains that were close to or exceeded those predicted after three years of treatment.

Growth followed a similar pattern in both extensive and poor metabolizers (EMs, PMs). PMs treated for at least 2 years gained an average of 2.4 kg and 1.1 cm less than predicted, while EMs gained an average of 0.2 kg and 0.4 cm less than predicted.

During acute treatment studies (up to 9 weeks), STRATTERA-treated patients lost an average of 0.4 kg, while placebo patients gained an average of 1.5 kg. In a controlled trial that randomized patients to placebo or 1 of 3 atomoxetine doses, 1.3%, 7.1%, 19.3%, and 29.1% of patients lost at least 3.5% of their body weight in the placebo, 0.5, 1.2, and 1.8 mg/kg/day STRATTERA dose groups, respectively. During acute treatment studies, STRATTERA-treated patients grew an average of 0.9 cm while placebo-treated patients grew an average of 1.1 cm. Whether final adult height or weight is affected by treatment with STRATTERA is unknown. Growth should be monitored during treatment with STRATTERA.

A study was conducted in young rats to evaluate the effects of atomoxetine on growth and neurobehavioral and sexual development. Rats were treated with 1, 10, or 50 mg/kg/day (approximately 0.2, 2, and 8 times, respectively, the maximum human dose on a mg/m² basis) of atomoxetine given by gavage from the early postnatal period (Day 10 of age) through adulthood. Slight delays in onset of vaginal patency (all doses) and preputial separation (10 and 50 mg/kg), slight decreases in epididymal weight and sperm number (10 and 50 mg/kg), and a slight decrease in corpora lutea (50 mg/kg) were seen, but there were no effects on fertility or reproductive performance. A slight delay in onset of incisor eruption was seen at 50 mg/kg. A slight increase in motor activity was seen on Day 15 (males at 10 and 50 mg/kg and females at 50 mg/kg) and on Day 30 (females at 50 mg/kg) but not on Day 60 of age. There were no effects on learning and memory tests. The significance of these findings to humans is unknown.

Atomoxetine HCl did not impair fertility in rats when given in the diet at doses of up to 57 mg/kg/day, which is approximately 6 times the maximum human dose on a mg/m² basis.

Atomoxetine HCl was not carcinogenic in rats and mice when given in the diet for 2 years at time-weighted average doses up to 47 and 458 mg/kg/day, respectively. The highest dose used in rats is approximately 8 and 5 times the maximum human dose in children and adults, respectively, on a mg/m² basis. Plasma levels (AUC) of atomoxetine at this dose in rats are estimated to be 1.8 times (extensive metabolizers) or 0.2 times (poor metabolizers) those in humans receiving the maximum human dose. The highest dose used in mice is approximately 39 and 26 times the maximum human dose in children and adults, respectively, on a mg/m² basis.

Although uncommon, allergic reactions, including rash, angioneurotic edema, and urticaria, have been reported in patients taking STRATTERA.

Particular care should be taken in treating ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in patients at risk for bipolar disorder. Prior to initiating treatment with STRATTERA, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

STRATTERA should be used with caution in patients with hypertension, tachycardia, congenital long QT syndrome, or cardiovascular or cerebrovascular disease because it can increase blood pressure and heart rate. Patients should be screened for pre-existing or underlying cardiovascular or cerebrovascular conditions before initiation of treatment with STRATTERA and monitored for new conditions of the heart or brain during the course of treatment. Pulse and blood pressure should be measured at baseline, following STRATTERA dose increases, and periodically while on therapy.

In pediatric placebo-controlled trials, STRATTERA-treated subjects experienced a mean increase in heart rate of about 6 beats/minute compared with placebo subjects. At the final study visit before drug discontinuation, 3.1% (16/518) of STRATTERA-treated subjects had heart rate increases of at least 25 beats/minute and a heart rate of at least 110 beats/minute, compared with 0.3% (1/338) of placebo subjects. 1.9% (10/518) of STRATTERA-treated subjects and 0.3% (1/338) of placebo subjects had a heart rate increase of at least 25 beats/minute and a heart rate of at least 110 beats/minute on 2 or more occasions. Tachycardia was identified as an adverse event for 0.5% (3/657) of these pediatric subjects compared with 0.0% (0/408) of placebo subjects. The mean heart rate increase in extensive metabolizer (EM) patients was 5.8 beats/minute, and in poor metabolizer (PM) patients 9.7 beats/minute.

STRATTERA-treated pediatric subjects experienced mean increases of about 1.5 mm Hg in systolic and diastolic blood pressures compared with placebo. At the final study visit before drug discontinuation, 5.2% (26/496) of STRATTERA-treated pediatric subjects had high systolic blood pressure measurements compared with 2.4% (8/327) of placebo subjects. High systolic blood pressures were measured on 2 or more occasions in 6.0% (30/496) of STRATTERA-treated subjects and 2.4% (8/327) of placebo subjects. At the final study visit before drug discontinuation, 3.0% (15/506) of STRATTERA-treated pediatric subjects had high diastolic blood pressure measurements compared with 0.9% (3/330) of placebo subjects. High diastolic blood pressures were measured on 2 or more occasions in 4.2% (21/506) of STRATTERA-treated subjects and 0.9% (3/330) of placebo subjects. (High systolic and diastolic blood pressure measurements were defined as those exceeding the 95th percentile, stratified by age, gender, and height percentile—National High Blood Pressure Education Working Group on Hypertension Control in Children and Adolescents.)

In adult placebo-controlled trials, STRATTERA-treated subjects experienced a mean increase in heart rate of 5 beats/minute compared with placebo subjects. Tachycardia was identified as an adverse event for 3% (8/269) of these adult atomoxetine subjects compared with 0.8% (2/263) of placebo subjects.

STRATTERA-treated adult subjects experienced mean increases in systolic (about 3 mm Hg) and diastolic (about 1 mm Hg) blood pressures compared with placebo. At the final study visit before drug discontinuation, 1.9% (5/258) of STRATTERA-treated adult subjects had systolic blood pressure measurements ≥150 mm Hg compared with 1.2% (3/256) of placebo subjects. At the final study visit before drug discontinuation, 0.8% (2/257) of STRATTERA-treated adult subjects had diastolic blood pressure measurements ≥100 mm Hg compared with 0.4% (1/257) of placebo subjects. No adult subject had a high systolic or diastolic blood pressure detected on more than one occasion.

Orthostatic hypotension has been reported in subjects taking STRATTERA. In short-term child- and adolescent-controlled trials, 5.2% (34/657) of STRATTERA-treated subjects experienced symptoms of postural hypotension compared with 2.0% (8/408) of placebo-treated subjects. STRATTERA should be used with caution in any condition that may predispose patients to hypotension.

There have been very rare reports of suicidal ideation, suicidal attempts, suicidal depression and completed suicides in children and adolescents (see Adverse Reactions, Post-Market Adverse Drug Reactions, Table 5 and Table 6).

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type of emotional and behavioural changes, and clinical worsening.

Risk of suicide-related behaviours and ideation in children (see also Warnings and Precautions, Potential Association with the Occurrence of Behavioural and Emotional Changes, Including Self-Harm).

Sudden deaths, stroke, and myocardial infarction have been reported in adults taking atomoxetine at usual doses for ADHD. Although the role of atomoxetine in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Consideration should be given to not treating adults with clinically significant cardiac abnormalities.

In adult ADHD controlled trials, the rates of urinary retention and urinary hesitation were increased among atomoxetine subjects compared with placebo subjects. A complaint of urinary retention or urinary hesitancy should be considered potentially related to atomoxetine.

Poor metabolizers (PMs) of CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose of STRATTERA compared with extensive metabolizers (EMs). Approximately 7% of a Caucasian population are PMs. Laboratory tests are available to identify CYP2D6 PMs. The blood levels in PMs are similar to those attained by taking strong inhibitors of CYP2D6. The higher blood levels in PMs lead to a higher rate of some adverse effects of STRATTERA (see Adverse Reactions).

Sudden death has been reported in association with atomoxetine treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, atomoxetine generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the noradrenergic effects of atomoxetine.

Routine laboratory tests are not required.

Post-marketing reports indicate that STRATTERA (atomoxetine) can cause severe liver injury in rare cases. Although no evidence of liver injury was detected in clinical trials of about 6000 patients, there have been rare cases in postmarketing experience of clinically significant liver injury that were considered probably or possibly related to STRATTERA. In one patient, liver injury, manifested by elevated hepatic enzymes (up to 40×upper limit of normal [ULN]) and jaundice (bilirubin up to 12×ULN), recurred upon rechallenge and was followed by recovery upon drug discontinuation, providing evidence that STRATTERA likely caused the liver injury. Such reactions may occur several months after therapy is started, but laboratory abnormalities may continue to worsen for several weeks after drug is stopped. Because of probable under-reporting, it is impossible to provide an accurate estimate of the true incidence of these events. The patient described above recovered from his liver injury, and did not require a liver transplant. However, severe liver injury due to any drug may potentially progress to acute liver failure resulting in death or the need for a liver transplant.

STRATTERA should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted. Laboratory testing to determine liver enzyme levels should be done upon the first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu-like” symptoms). (See also Information for the Patient.)

Atomoxetine HCl was negative in a battery of genotoxicity studies that included a reverse point mutation assay (Ames Test), an in vitro mouse lymphoma assay, a chromosomal aberration test in Chinese hamster ovary cells, an unscheduled DNA synthesis test in rat hepatocytes, and an in vivo micronucleus test in mice. However, there was a slight increase in the percentage of Chinese hamster ovary cells with diplochromosomes, suggesting endoreduplication (numerical aberration).

The metabolite N-desmethylatomoxetine HCl was negative in the Ames Test, mouse lymphoma assay, and unscheduled DNA synthesis test.

Aggressive behaviour or hostility has been observed in children and adolescents with ADHD, and has been reported with some medications indicated for the treatment of ADHD. Although there is no conclusive evidence that atomoxetine causes aggressive behaviour or hostility, this was observed more frequently in clinical trials among children and adolescents treated with atomoxetine compared to placebo (overall risk ratio of 1.33—not statistically significant). Patients beginning treatment for ADHD should be monitored for the appearance of, or worsening of, aggressive behaviour or hostility.

Caregivers/patients should be instructed to call their doctor as soon as possible should they notice an increase in aggression or hostility.

Atomoxetine and/or its metabolites were excreted in the milk of rats. It is not known if atomoxetine is excreted in human milk. Caution should be exercised if STRATTERA is administered to a nursing woman.

The steady-state volume of distribution after intravenous administration was approximately 0.85 L/kg indicating that atomoxetine distributes primarily into total body water. In children and adolescents, volume of distribution increased nearly proportionally to increases in body weight. Volume of distribution is similar across the patient weight range after normalizing for body weight.

At therapeutic concentrations, 98% of atomoxetine in plasma is bound to protein, primarily albumin.

Atomoxetine is well-absorbed after oral administration and is minimally affected by food. It is eliminated primarily by oxidative metabolism through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway and subsequent glucuronidation. Atomoxetine has a half-life of about 5 hours. A fraction of the population (about 7% of Caucasians and 2% of African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of 21.6 hours) of atomoxetine compared with people with normal activity [extensive metabolizers (EMs)]. Drugs that inhibit CYP2D6, such as fluoxetine, paroxetine, and quinidine, cause similar increases in exposure.

The pharmacokinetics of atomoxetine have been evaluated in more than 400 children and adolescents in selected clinical trials using a population approach. Single-dose and steady-state individual pharmacokinetic data were also obtained in children, adolescents, and adults. When doses were normalized to a mg/kg basis, similar half-life, C_max, and AUC values were observed in children, adolescents, and adults. Clearance and volume of distribution after adjustment for body weight were also similar.

Atomoxetine pharmacokinetics are dose proportional within the therapeutic range; hence, administration of STRATTERA once- or twice-daily is expected to result in the same systemic exposure (AUC) over a 24-hour period. Results of efficacy analysis show that once-daily (QD) dosing with STRATTERA is efficacious in the treatment of ADHD.

STRATTERA 80 mg capsules are bioequivalent to 2x40 mg capsules. STRATTERA 100 mg capsules are bioequivalent to a combination of one 40 mg and one 60 mg capsule.

Atomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in extensive metabolizers (EMs) and 94% in poor metabolizers (PMs). Mean maximal plasma concentrations (C_max) are reached approximately 1 to 2 hours after dosing.

STRATTERA can be administered with or without food. In clinical trials with children and adolescents, administration of STRATTERA with food resulted in a 9% lower C_max. Administration of STRATTERA with a standard high-fat meal in adults did not affect the extent of oral absorption of atomoxetine (AUC), but did decrease the rate of absorption, resulting in a 37% lower C_max and delayed T_max by 3 hours.

The mean elimination half-life of atomoxetine after oral administration is 5.2 hours and 21.6 hours in EM and PM subjects, respectively. The elimination half-life of 4 hydroxyatomoxetine is similar to that of N-desmethylatomoxetine (6 to 8 hours) in EM subjects, while the half-life of N-desmethylatomoxetine is much longer in PM subjects (34 to 40 hours).

Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine (greater than 80% of the dose) and to a lesser extent in the feces (less than 17% of the dose). Only a small fraction (less than 3%) of the STRATTERA dose is excreted as unchanged atomoxetine, indicating extensive biotransformation.

Gender did not influence atomoxetine disposition.

Atomoxetine undergoes biotransformation primarily through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway. People with reduced activity in the CYP2D6 pathway (PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (EMs). For PMs, AUC of atomoxetine at steady-state is approximately 10-fold higher and C_ss,max is about 5-fold greater than for EMs.

Coadministration of STRATTERA with potent inhibitors of CYP2D6, such as fluoxetine, paroxetine, or quinidine, results in a substantial increase in atomoxetine plasma exposure, and dosing adjustment may be necessary (see Drug Interactions, Drug-Drug Interactions). In EM patients treated with potent CYP2D6 inhibitors such as fluoxetine, and paroxetine, the AUC of atomoxetine is approximately 6- to 8-fold and C_ss,max is about 3- to 4-fold greater than with atomoxetine alone.

In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentration of atomoxetine.

Atomoxetine did not inhibit or induce the CYP2D6 pathway.

The major oxidative metabolite formed regardless of CYP2D6 status is 4-hydroxyatomoxetine, which is rapidly glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter, but circulates in plasma at much lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentration in PMs). 4-Hydroxyatomoxetine is primarily formed by CYP2D6. In individuals that lack CYP2D6 activity (poor metabolizers), 4-hydroxyatomoxetine is formed by several other cytochrome P450 enzymes, but at a slower rate. N-Desmethylatomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has much less pharmacological activity than atomoxetine, and plasma concentrations are lower (5% of atomoxetine concentration in EMs and 45% of atomoxetine concentration in PMs).

There are two major phenotypes associated with CYP2D6: extensive metabolizers that comprise >90% of the population, and poor metabolizers. Approximately 7% of the Caucasian population and 2% of Black population are poor metabolizers of CYP2D6.

In ex vivo uptake and neurotransmitter depletion studies, atomoxetine was found to selectively inhibit the pre-synaptic norepinephrine transporter without directly affecting the serotonin or dopamine transporters. Atomoxetine has minimal affinity for other receptor systems. Atomoxetine is primarily oxidized to 4-hydroxyatomoxetine, which is also a potent inhibitor of the pre-synaptic norepinephrine transporter.

The pharmacokinetics of atomoxetine in children and adolescents are similar to those in adults. The pharmacokinetics of atomoxetine have not been evaluated in children under 6 years of age.

The pharmacokinetics of atomoxetine have not been systematically evaluated in the geriatric population.

Single doses of STRATTERA administered to EM subjects with moderate to severe hepatic insufficiency (Child-Pugh Class B and C) resulted in increased atomoxetine exposure, reduced atomoxetine clearance, and prolonged half-life of parent drug compared with healthy subjects. Dosage adjustment is recommended for patients with moderate or severe hepatic impairment (see Dosage and Administration).

STRATTERA (atomoxetine hydrochloride) is a selective norepinephrine reuptake inhibitor. Its therapeutic effect in ADHD is thought to be related to its potent inhibition of the pre-synaptic norepinephrine transporter, with minimal affinity for other noradrenergic receptors or for other neurotransmitter transporters or receptors.

Study LYAS enrolled patients meeting DSM-IV criteria for ADHD and comorbid Tourette’s Disorder or chronic motor tics. STRATTERA met the primary study objective of non-inferiority to placebo with respect to worsening of tics and had a beneficial effect in reducing tic severity. STRATTERA was also markedly superior to placebo in reducing symptoms of ADHD as assessed by the ADHDRS-IV-Parent: Inv Total score (p=0.002).

Ethnic origin did not influence atomoxetine disposition.

Single doses of STRATTERA administered to EM subjects with end stage renal disease resulted in higher atomoxetine exposure (AUC) than in healthy subjects (about a 65% increase), but there was no difference when exposure was corrected for mg/kg dose. STRATTERA can therefore be administered to ADHD patients with end stage renal disease or lesser degrees of renal insufficiency using the normal dosing regimen.

The safety and tolerability of gradually increasing multiple-dose regimes of atomoxetine 60 to 150 mg/day was studied in 16 healthy adults (10 EM subjects and 6 PM subjects). None of the mean or individual QT_c(F) intervals exceeded the upper limits of normal for each gender. The EM group had no statistically significant changes in mean QT_c(F) interval compared to the placebo treatment. No statistically significant changes in QT_c(F) were noted 1 hour post dose (during peak plasma concentrations) in the PM group. The PM group had a statistically significant increase in the mean QT_c(F) interval measured at time 0 (during trough plasma concentrations) on the last day of the 60- and 75-mg atomoxetine twice-daily dosing regimens compared to the placebo. The greatest mean prolongation was about 17 msec at the 60-mg BID dose level, with the mean interval length of 417.2 msec. At the 75-mg BID atomoxetine dose level, the greatest mean prolongation was 15 msec, and the mean interval length was 414.9 msec. The 60 mg BID and 75 mg BID doses correspond to 1.4-2.24 mg/kg/day and 1.75-2.8 mg/kg/day, respectively. Baseline ECGs obtained during screening of pediatric patients for atomoxetine clinical trials were reviewed for cases of QTc prolongation. Using a correction method based on data from baseline ECGs, there were 32/3902 cases (0.8%) with QT_c(D) >450 msec and 5/3902 cases (0.1%) with QT_c(D)>500 msec. In a meta-analysis of ECG data from patients who received atomoxetine in pediatric clinical trials, no relationship was observed between changes from baseline to final QT_c(D) and prescribed atomoxetine dose, or between changes from baseline to QT_c(D) at time of expected peak exposure and prescribed atomoxetine dose.

Overall, the data do not suggest a meaningful relationship between atomoxetine plasma concentrations and the length of the QT interval corrected for heart rate in the recommended dosage range. However, since there is no requirement for a priori screening of ADHD patients for CYP2D6 metabolizer status before initiating treatment with atomoxetine, it is important that the lowest effective dose be used, so as to minimize potential cardiac side effects.

Adult patients (n=442, age 18-65) , who met DSM-IV criteria for adult ADHD and social anxiety disorder (23% of whom also had Generalized Anxiety Disorder) were randomized into a 16-week double-blind, placebo-controlled trial. The statistical analysis plan specified that patients responding (i.e., >25% decrease in social anxiety symptoms as measured by the Liebowitz Social Anxiety Scale) during a blinded placebo lead-in period be excluded from the primary efficacy analyses. However, all of the enrolled patients with a baseline and at least one post-baseline score were included in the remaining efficacy analyses. STRATTERA was initiated at 40 mg/day to a maximum dose of 100 mg/day (mean daily dose 83 mg/day ± 9.5 mg/day). STRATTERA was markedly superior to placebo in reducing symptoms of ADHD as assessed by the Conners’ Adult ADHD Rating Scale (p <0.001). Worsening of anxiety was defined post-hoc as a 25% increase in LSAS, or patient-reported anxiety as an adverse event. Based on these criteria, patients on STRATTERA did not have worsening of anxiety relative to the placebo group. Of the 436 patients who completed the double-blind placebo lead-in, 172 (39%) discontinued the study.

Pediatric patients (n=176, age 8-17), who met DSM-IV criteria for ADHD and at least one of the anxiety disorders of separation anxiety disorder, generalized anxiety disorder or social phobia were randomized 1:1 into a 12-week double-blind, placebo-controlled trial. The statistical analysis plan specified that patients responding (i.e., >25% reduction in Pediatric Anxiety Rating Scale (PARS) total scores) during a blinded placebo lead-in period be excluded from the primary efficacy analyses. However, all of the enrolled patients with a baseline and at least one post-baseline score were included in the remaining efficacy analyses. Initial STRATTERA dose was 0.8 mg/kg/day, with increase to a target dose of 1.2 mg/kg/day (median dose 1.3 mg/kg/day ± 0.3 mg/kg/day). STRATTERA was markedly superior to placebo in reducing symptoms of ADHD as assessed by the ADHDRS-IV-Parent: Inv Total score (p <0.001). Worsening of anxiety was defined post-hoc as a 25% increase in PARS, or patientreported anxiety as an adverse event. Based on these criteria, patients on STRATTERA did not have worsening of anxiety relative to the placebo group. Of the 158 patients who completed the double-blind placebo lead-in, 26 (16%) discontinued the study.